Small-molecule cyclin-dependent kinase modulators

ABSTRACT Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an

important component in the G1/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases

(cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two

classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include

flavopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include

perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle

arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least

three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions ⩾24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients

receiving shorter infusions have nausea/vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently

completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens

containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these

encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of

direct small-molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca2+-dependent PKCs, promotes

apoptosis, arrests cell cycle progression at G1/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel

feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks (in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h)

are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being

tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule

cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in

advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies. Access through your institution Buy or subscribe This is a

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INHIBITORS INDUCE SELECTIVE AND IMMEDIATE DISSOCIATION OF P21 FROM CYCLIN D-CDK4 TO INHIBIT CDK2 Article Open access 07 June 2021 TARGETING CYCLIN-DEPENDENT KINASE 9 IN CANCER THERAPY

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Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, 20892-4330, MD, USA Adrian M Senderowicz Authors * Adrian M

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Senderowicz, A. Small-molecule cyclin-dependent kinase modulators. _Oncogene_ 22, 6609–6620 (2003).

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Springer Nature SharedIt content-sharing initiative KEYWORDS * cell cycle * molecular targets * cyclin-dependent kinases * flavopiridol * UCN-01 * CYC202 * BMS 387032 * drug development